Drug quickly reverses Alzheimer's symptoms in mice

- It has already been approved by the FDA. In fact, it has been used to fight cancer for over a decade, and already has a track record for safety. Because of this, it could be in use for Alzheimer's as much as five years sooner than a new drug.

- Researchers were struck by the speed with which bexarotene improved memory deficits and behavior in mice and reversed the pathology of Alzheimer's disease.

- Within three days of drug treatment, the number of plaques in the brain (which builds up in brains of Alzheimer's patients) was reduced by more than half. In Other Words, this Drug Was Given to Mice with Alzheimer's Disease...and They Got Better.

The Discovery

Neuroscientists at Case Western Reserve University School of Medicine have made a dramatic breakthrough in their efforts to find a cure for Alzheimer's disease. The researchers' findings, published in the journal Science, show that use of a drug in mice appears to quickly reverse the pathological, cognitive and memory deficits caused by the onset of Alzheimer's. The results
point to the significant potential that the medication, bexarotene, has to help the roughly 5.4 million Americans suffering from the progressive brain disease.

Bexarotene has been approved for the treatment of cancer by the U.S. Food and Drug Administration for more than a decade. These experiments explored whether the medication might also be used to help patients with Alzheimer's disease, and the results were more than promising.

Alzheimer's disease arises in large part from the body's inability to clear naturally-occurring amyloid beta from the brain. In 2008 researcher Gary Landreth, PhD, professor of neurosciences, discovered that the main cholesterol carrier in the brain, Apolipoprotein E (ApoE), facilitated the clearance of the amyloid beta proteins. Landreth, a professor of neurosciences in the university's medical school, is the senior author of this study as well.

Landreth and his colleagues chose to explore the effectiveness of bexarotene for increasing ApoE expression. The elevation of brain ApoE levels, in turn, speeds the clearance of amyloid beta from the brain. Bexarotene acts by stimulating retinoid X receptors (RXR), which control how much ApoE is produced.

Rapid Results

In particular, the researchers were struck by the speed with which bexarotene improved memory deficits and behavior even as it also acted to reverse the pathology of Alzheimer's disease. The present view of the scientific community is that small soluble forms of amyloid beta cause the memory impairments seen in animal models and humans with the disease. Within 6 hours of administering bexarotene, however, soluble amyloid levels fell by 25 percent; even more impressive, the effect lasted as long as three days. Finally, this shift was correlated with rapid improvement in a broad range of behaviors in three different mouse models of Alzheimer's.

One example of the improved behaviors involved the typical nesting instinct of the mice. When Alzheimer's-diseased mice encountered material suited for nesting – in this case, tissue paper – they did nothing to create a space to nest. This reaction demonstrated that they had lost the ability to associate the tissue paper with the opportunity to nest. Just 72 hours after the bexarotene treatment, however, the mice began to use the paper to make nests. Administration of the drug also improved the ability of the mice to sense and respond to odors.

Bexarotene treatment also worked quickly to stimulate the removal of amyloid plaques from the brain. The plaques are compacted aggregates of amyloid that form in the brain and are the pathological hallmark of Alzheimer's disease. Researchers found that more than half of the plaques had been cleared within 72 hours. Ultimately, the reduction totaled 75 percent. It appears that the bexarotene reprogrammed the brain's immune cells to "eat" or phagocytose the amyloid deposits. This observation demonstrated that the drug addresses the amount of both soluble and deposited forms of amyloid beta within the brain and reverses the pathological features of the disease in mice.

Potential New Therapy

This study identifies a link between the primary genetic risk factor for Alzheimer's disease and a potential therapy to address it. Humans have three forms of ApoE: ApoE2, ApoE3, and ApoE4.

Possession of the ApoE4 gene greatly increases the likelihood of developing Alzheimer's disease. Previously, the Landreth laboratory had shown that this form of ApoE was impaired in its ability of clear amyloid. The new work suggests that elevation of ApoE levels in the brain may be an effective therapeutic strategy to clear the forms of amyloid associated with impaired memory and cognition.

"This is an unprecedented finding," says Paige Cramer, PhD candidate at Case Western Reserve School of Medicine and first author of the study. "Previously, the best existing treatment for Alzheimer's disease in mice required several months to reduce plaque in the brain."

Added Professor Landreth: "This is a particularly exciting and rewarding study because of the new science we have discovered and the potential promise of a therapy for Alzheimer's disease. We need to be clear; the drug works quite well in mouse models of the disease. Our next objective is to ascertain if it acts similarly in humans. We are at an early stage in translating this basic science discovery into a treatment."

Daniel Wesson, PhD, assistant professor of neurosciences at Case Western Reserve School of Medicine and co-author of the study agreed.

"Many often think of Alzheimer's as a problem of remembering and learning, but the prevalent reality is this disease spreads throughout the brain, resulting in serious insults to numerous functions," he said. "The results of this study, showing the preservation of behaviors across a wide spectrum, and accompanying brain function, are tremendously exciting and suggest great promise in the utility of this approach in treatment of Alzheimer's disease."

Bexarotene has a good safety and side-effect profile. The Case Western Reserve researchers hope these attributes will help speed the transition to clinical trials of the drug.

Professor Landreth said modest resources funded this self-described "far-fetched idea." Crucial support came from the Blanchette Hooker Rockefeller Foundation, the Thome Foundation, and the National Institutes of Health. The Science study was co-authored by John R. Cirrito, Jessica L. Restivo, Whitney D. Goebel, Washington University School of Medicine; C.Y. Daniel Lee, Colleen Karlo, Adriana E. Zinn, Brad T. Casali, Case Western Reserve University School of Medicine; Donald A. Wilson, New York University School of Medicine, and Michael J. James, Kurt R. Brunden, Perelman School of Medicine, University of Pennsylvania.

What's Next?

The Landreth lab is currently investigating how best to deliver bexarotene. Preliminary work demonstrates that the drug will be optimally effective at levels lower than the FDA-approved dosage. Moreover, we do not know how frequently to administer the drug to mice. This work is essential before advancing to Phase II clinical trials and will take some time to complete. We are also investigating new drug candidates.

Researchers have discovered that an injection of a protein called IL-33 can reverse Alzheimer's-like symptoms and cognitive decline in mice, restoring their memory and cognitive function to the same levels as healthy mice in the space of one week.

Mice bred to develop a progressive Alzheimer's-like disease as they aged (called APP/PS1 mice) were given daily injections of the protein, and it appeared to not only clear out the toxic amyloid plaques that are thought to trigger Alzheimer’s in humans, it also prevented more from forming.

"IL-33 is a protein produced by various cell types in the body and is particularly abundant in the central nervous system (brain and spinal cord)," says lead researcher, Eddy Liew from the University of Glasgow in the UK. "We found that injection of IL-33 into aged APP/PS1 mice rapidly improved their memory and cognitive function to that of the age-matched normal mice within a week. Before we go any further, we should make it clear that these results are restricted to mice only, and at this stage, we have no idea if they will translate at all in humans with Alzheimer’s."

And the odds aren’t great - one study put successful translation of positive results in mice to humans at a rate of about 8 percent, so we can never get too excited until we see how things fare in human trials. But when it comes to a disease with no known cure that’s expected to affect 65 million people by 2030, any new development is worth a look at, and the team behind the discovery reports "encouraging hints" that certain aspects of this study could translate to human Alzheimer's patients.

In humans, Alzheimer’s disease usually results from a build-up of two types of lesions in the brain - amyloid plaques, and neurofibrillary tangles.

Amyloid plaques sit between the neurons and form dense clusters of a sticky type of protein called beta-amyloid.

Neurofibrillary tangles are found inside the neurons, caused by defective tau proteins that clump up into a thick, insoluble mass. This causes tiny filaments called microtubules to get twisted, which disrupts the transportation of essential nutrients around the brain.

"Right now, no one knows why certain people experience a build-up of amyloid plaques and neurofibrillary tangles in the brain as they age, and others don’t, but scientists are confident that if we can figure out how to clear them out and stop them forming, we can effectively treat the disease."

Working with mice, Liew and his team discovered that IL-33 appears to kickstart immune cells in the brain called microglia, directing them towards the toxic amyloid plaques. Once the plaques were on their radar, the microglia aggressively targeted and absorbed them with the help of an enzyme called neprilysin, which is known to break down soluble amyloid.

This process was found to reduce the size and number of amyloid plaques in mice with Alzheimer’s-like symptoms. Not only that, but the IL-33 injections also prevented inflammation in the brain tissue, which previous studies have linked to the proliferation of plaques and neurofibrillary tangles.

"Therefore IL-33 not only helps to clear the amyloid plaque already formed, but also prevent the deposition of the plaques and tangles in the first place," the Glasgow team reports.

So it's good news for APP/PS1 mice everywhere, and a very interesting result for researchers around the world who are hell-bent on finding a cure or treatment for Alzheimer’s disease in humans. Liew remains cautiously optimistic:

"The relevance of this finding to human Alzheimer’s is at present unclear. But there are encouraging hints. For example, previous genetic studies have shown an association between IL-33 mutations and Alzheimer’s disease in European and Chinese populations. Furthermore, the brain of patients with Alzheimer’s disease contains less IL-33 than the brain from non-Alzheimer’s patients."

He adds that, "There have been enough false 'breakthroughs' in the medical field to caution us not to hold our breath until rigorous clinical trials have been done," but says they’re just about to enter a Phase 1 clinical trial with human patients to test the toxicity of IL-33 at the doses used in mice. "We’re ready and waiting for those results."

The research has been published in Proceedings of the National Academy of Sciences.

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